Neurogenesis in mammals is complete early in the postnatal period. Cells of the adult mammalian central nervous system (CNS) have little or no ability to undergo mitosis and generate new neurons. Thus, the generation of new CNS neurons in adult primates does not normally occur. This inability to produce new nerve cells in most mammals (and especially primates) may be advantageous for long-term memory retention; however, it is a distinct disadvantage when the need to replace lost neuronal cells arises due to injury or disease.
CNS disorders encompass numerous afflictions such as neurodegenerative diseases (e.g. Alzheimer's and Parkinson's), acute brain injury (e.g. stroke, head injury, cerebral palsy) and a large number of CNS dysfunctions (e.g. depression, epilepsy, and schizophrenia). Degeneration in a brain region known as the basal ganglia can lead to diseases with various cognitive and motor symptoms, depending on the exact location. Other forms of neurological impairment can occur as a result of neural degeneration, such as cerebral palsy, or as a result of CNS trauma, such as stroke and epilepsy. In the case of Alzheimer's disease, there is a profound cellular degeneration of the forebrain and cerebral cortex. In the case of Parkinson's disease, degeneration is seen in the substantia nigra par compacta. This area normally sends dopaminergic connections to the striatum that are important in regulating movement. Dopamine is a catecholamine neurotransmitter that is particularly important in the control of movement. The great majority of brain dopamine is found in the striatum, and contained in neurons originating from a brain stem nucleus, the substantia nigra. The death of these cells, with a consequent loss of dopamine, is responsible for the symptoms of Parkinson's disease. Other dopaminergic neurons of the brain stem innervate the limbic system and cortex and abnormalities of these systems have been implicated in schizophrenia. Therapy for Parkinson's disease has centered upon restoring dopaminergic activity to this circuit through the use of pharmaceutical compounds and/or neurotrophic factors.
Neurotrophic factors are polypeptides that variously support the survival, proliferation, differentiation, size, and function of nerve cells. Most trophic factors can be assigned to one or another established family based upon their structure or binding affinities. Growth factors from various families, including the epidermal growth factor (EGF) family, have been demonstrated to support growth and differentiation of dopaminergic neurons of the nigrostriatal system. EGF has been localized to areas of the developing adult forebrain and to areas of the midbrain such as the globus pallidus, ventral pallidum, entopeduncular nucleus, substantia nigra, and the Islands of Calleja. The EGF receptor was localized by immunocytochemistry to astrocytes and subpopulations of cortical and cerebellar neurons in rat brain and to neurons in human autopsy brain specimens.
Transforming growth factor-alpha (TGF-α) is a member of the EGF family that has been shown to bind the EGF receptor, stimulate the receptor's tyrosine kinase activity, and elicit similar mitogenic responses in a wide variety of cell types. TGF-α also supports the survival of mesencephalic dopamine neurons in dissociated cell culture and supports the survival of cultured central neurons.
Treatment of CNS disorders has focused not only on the administration of trophic factors, but also on the administration of stem cells to replace those neural cells lost by natural cell death, injury or disease. For example, multipotent neural stem cells that are capable of producing progeny that differentiate into neurons and glia exist in adult mammalian neural tissue. Moreover, recent studies indicate that neuronal tissue can be generated from cells derived from adult bone marrow. These studies demonstrate that transplanted adult bone marrow stem cells can differentiate into neuronal cells.
Despite recent advances in treating neurological deficits, treatments still require the direct application of a trophic factor or infusion of stem cells to a site of injury or damage in the CNS in a subject in need of such treatment. Given the paucity of successful treatments for neurological deficits in general, there remains a need for additional methods that do not rely on invasive intracranial procedures or exogenous stem cells to achieve a result.
Literature
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